Fluorenyl and benzohydryl esters



/ Reissued Aug. 14, 1951 FLUORENYL AND BENZOHYDRYL ESTERS AND METHOD OF PRODUCING THEM John W. Cusic, Skokie, and Richard A. Robinson, Morton Grove, IlL, assignors to G. D. Searle & 00., Skokie, Ill., a corporation of Illinois No Drawing. Original No. 2,480,224, dated August 30, 1949, Serial No. 738,501, March 31, 1947. Applicgtion for reissue July 19, 1950, Serial No.

14 Claims.

This invention relates to a group of esters of amino-substituted lower alkanoic acids with diaryl carbinols. In particular it relates to compounds having the formula CH---C0-Alk- -B Ar wherein Ar and Ar are aryl radicals, All: is a lower alkylene radical, and B is a secondary or tertiary aliphatic amino radical.

In the above formula, Ar and Ar represent simple aryl radicals such as phenyl, tolyl, chlorophenyl, bromophenyl, anisyl, naphthyl, xenyl and the like, and aromaticheterocyclic radicals such as thienyl, pyridyl, furyl and related groups.

Ar and Ar together can form an arylene group such as the o-biphenylene radical, which together with the CH radical comprises a 9-fluorenyl radical. Other similar diarylmethyl radicals which are within the scope of our invention include 9-xanthyl, IO-thioxanthyl, and 9,10-dihydro-IO-anthryl. The secondaryand tertiaryamino substituted lower alkanoic acids which make up the acid portion of the compounds include beta-secondaryand tertiary-aminopropionic acids such as the lower beta-monoand dialkylaminopropionic acids, beta-piperidinepropicnic acid, beta-pyrrolidinopropionic acicL'bstamorpholinopropionic acid and alkyl derivatives of these acids; betaand gamma-secondaryand tertiary-aliphatic-aminobutyric and valeric acidsot the same type wherein the amino group is derived from a strong primary or secondary, organic base of the aliphatic series or of the aliphatic-type heterocyclic series which'has an ionization constant in the range of about 10- to 10- It will be seen that Alk in the above formula represents a lower alkylene radical such as ethylene, propylene, trimethylene, 1,2- and 2,3-butylene and similar radicals. It will be seen further that the basic group 13 represents an aprimary aliphatic amino radical such as the lower monoand dialkylamino groups and simple heterocyclic amino groups as represented by those derived from morpholine, piperidine, pyrrolidine, alphamethylpiperidine and other aliphatic-type secondary amines.

Among the compounds which comprise our in vention are the following:

(a) Benzohydryl beta-methylethylaminobutyrate, which has the formula CsHs CH3 011-041 o-Cmou-moru) 02m CQHI (Cl. 260-48Z) Matter enclosed in heavy brackets I: appears in the original patent but forms no part of this reissue specification; matter printed in italics indicates the additions made by reissue.

2 It is prepared by esterifying benzohydrol with beta-chlorobutyric acid and reacting the resulting ester with methylethylamine.

(b) Phenyl-o-tolylcarbinyl gamma-N-pyrrolidinobutyrate, which has the formula G gs CHzOH: OH-O-O o-omcmcur-N CH3CeH4 CH2 H2 This is prepared from p-anisylphenylcarbinol (obtained by reduction of the methoxybenzophenone) and beta-chlorovaleric acid by esterification and subsequent treatment of the ester with excess methylamine.

(d) 9,10'-dihydro 9 anthryl beta-piperidinopropionate, which has the formula Anthrone is reduced to 9,10-dlhydro-9-anthrol and the latter is converted to the ester with betabromopropionic acid. The halogenated ester is then condensed with piperidine to form the amino ester. v

(e) 9-xanthyl gamma -propylaminobutyrate, which has the formula Xanthone is reduced to 9-xanthol, the latter is esterified with gamma-chlorobutyric acid and the resulting halogenated ester is reacted with propylamine.

(f) p-Xenyl-p-chlorophenylcarbinyl beta-(2- formula The compounds which comprise our invention are useful in therapeutics, particularly as antispasmodic agents. They exert a powerful relaxing effect on strips of living smooth'muscle tissue which have previously been brought into a state of spastic contraction by the action of such agents as histamine, acetylcholine, or barium chloride.

The esters of this invention may be prepared by reacting a halogen-substituted fatty acid with the desired diarylcarbinol and further reacting the halogen ester thus obtained with a primary or secondary amine to form the desired amino acid ester. A preferred process of preparing the diarylmethyl esters of the haloalkanoic acids comprises heating together equivalent quantities of the diarylcarbinol and haloalkanoic acid in the presence of benzene or toluene'or other water-immiscible solvents having a boiling point relatively close. to that of water, in such a way that a mixture of water and the water-immiscible solvent distils from the reaction mixture. This procedure provides a simple and highly efficient process for the preparation of the desired intermediate esters. The conversion of these halogenated esters into the amino esters which comprise our invention may be carried out by heating the halogenated ester with an excess of a primary or secondary amine in the presence or absence of a solvent, using a closed system when necessary to retain volatile material. The amino esters are only sparingly soluble in water but readily form salts with acids, which salts are generally readily water-soluble. Among the acids which are suitable for forming salts of these bases arehydrochloric, hydrobromic, sulfuric, phosphoric, tartaric, citric, acetic, and similar common acids which provide non-toxic anions. These salts are generally crystalline solids, and since they manifest the same therapeutic; properties as the free bases they constitute a preferred form for the use of these compounds. It will be understood that the appended claims include the basic esters whether they be in the form of the free bases or in the form of saltsthereof.

Our invention is further disclosed-by the following examples, which are merely illustrative in nature and which in no way limit our invention.

EXAMPLE 1 A mixture of 35.8 g. of benzohydrol, 25.4 g. of beta-chloropropionyl chloride, 24.2 g. of dimethylaniline and 400 'cc. of benzene is refluxed overnight. The reaction mixture is extracted with dilute hydrochloric acid. The benzene ,solution is dried with anhydrous calcium chloride and evaporated. 27 g. of the crude -benzohydryl beta-chloropropionate thus obtained is heated in a sealed tube with 15 g. of diethylamine at 100 C. for 8 hours. The tube is opened and its contents are washed out with dilute hydro-- chloric acid. This solution is extracted with ether to remove non-basic material. It is then made alkaline and extracted with ether. The ether extract is washed, dried with anhydrous sodium sulfate, and evaporated. The residue disti led;

4 B. P. 190-195 C. at 4 mm. The free base, when dissolved in dry ether and treated with saturated alcoholic hydrogen chloride, forms benzohydryl b e t a diethylaminopropionate hydrochloride which melts at 174 C. after recrystallization from isopropanol. Treatment of the base with ethyl bromide in methyl ethyl ketone at 0. results in the formation of the ethobromide of M. P. 152 C.

By reacting benzohydryl beta-chloropropionate with dimethylamine by a process similar to the above, there is obtained benzohydryl-betadimethylaminopropionate hydrochloride of M. P. 154l55 C. Treatment of benzohydryl beta-dimethylaminopropionate with methyl chloride in methyl ethyl ketone results in the formation of the methochloride, M. P. -145 0.

EXAMPLE 2 A solution of 35.6 g. of Q-fluorenol, 25.4 g. of beta-chloropropionyl chloride, 24.2 g. of dimethylaniline and 500 cc. of dry benzene is heated to reflux for 12 hours. The reaction mixture is extracted with dilute hydrochloric acid, Washed with water, and dried over anhydrous calcium chloride. The solvent is removed by evapora tion and heating in vacuo on a steam bath. 27.2

g. of Q-fluorenyl beta-chloropropionate is heated,

hydrochloride may be prepared from a dry ethereal solution of the base by addition of alcoholic hydrogen chloride, and melts at 1'71-1'22' C. after recrystallization from isopropanol.

By heating in a closed system at 100 C. for

8 hours 22 g. of 9-fluorenyl beta-chloropropionate,

10 g. of dimethylamine and '75 cc. of toluene,

there is produced 9-fluorenyl beta-dimethyl aminopropionate, which is isolated as in the above example. It distils at 195-200" C. at 1-2 mm. and forms a hydrochloride melting at 183- EXAMPLE 3 A solution of 23.4 g. of phenyl-alpha-naphthylcarbinol and 7.9 g. of pyridine in benzene is cooled and treated with 12.7 g. of beta-chloropropionyl chloride in benzene.

solid. The addition of ether and water causes the solution of this precipitate and the formation of two layers. The organic layer is separted; washed with water, and dried with anhydrous calcium chloride.

with a solution of 17 g. of piperidine in cc. of toluene. The precipitate is removed by filtration. The filtrate is evaporated to remove toluene and piperidine. The cooled residue is taken up in ether and treated with alcoholic hydrogen chloride. The precipitated hydrochloride is removed by filtration, washed with ether, dried in vacuo,. and; recrystallized from isopropanol..

Pheny1 alpha naphthylcarbinyl beta-N-piperidinopropionatehydrochloride melts at 200-. 201 C.

EXAMPLE 4 A solution of 27.4 g. of benzohydryl beta-ch10- wpr p naie Eiia p e l.) nd. .7.. s. of morp There is an immediate precipitate-which upon standing becomes The solvent is removed andthe crude ester remaining is refluxed overnight line in 100 cc. of toluene is refluxed for 5 hours. The morpholine hydrochloride is removed by filtration and the filtrate is evaporated and distilled under reduced pressure, resulting in benzohydryl beta-N-morpholinopropionate of B. P. ZOO-220 C. at 2-3 mm. The hydrochloride is prepared by treatment of a dry ether solution of the base with alcoholic hydrogen chloride, and melts at 180- 181 C. after recrystallization from isopropanol.

By using an equivalent amount of piperidine in the above example, there is obtained benzohydryl beta-N-piperidinopropionate, B. P. 180-210 C. at

3 mm., which forms a hydrochloride melting at 193-194 C. after recrystallization from isopropanol.

EXAMPLE 5 A solution of 54.2 g. of beta-chloropropionic acid and 92 g. of benzohydrol in 400 cc. of toluene is refluxed. The condensate is returned to the reaction vessel via a water separator. In 3 hours 7 cc. of water is collected and overnight an additional 1 cc. of water is obtained (89% of theory). The toluene is then removed by distillation and benzohydryl beta-chloropropionate, B, P. 195- 210 C. at 10-12 mm, is obtained in excellent yield. Condensation of this chloro ester with pyrrclidine as in Example 1 results in th formation of benzohydryl beta-N-pyrrolidinopropionate. Similarly, condensation of benzohydryl beta-chloropropionate with excess butylamine gives rise to benzohydryl beta-butylaminopropionate.

We claim:

1. A 9-fluorenyl ester of a beta-lower-dialkylaminopropionic acid, which has the formula wherein R and R are lower alkyl radicals.

2. 9-fluoreny1 beta-dimethylaminopropionate.

3. The process of producing a Q-fluorenyl ester of a lower tertiary-aliphatic-aminoalkanoic acid which comprises esterifying a lower haloalkanoic acid with a 9-f1uorenol and reacting the ester thus formed witha secondary aliphatic amine.

4. In a process of producing a Q-fiuorenyl ester of a lower tertiary-aliphatic-aminoalkanoic acid, the step which comprises esterifying a lower haloalkanoic acid with a 9-fiuorenol with the simultaneous removal of water by continuous distillation with a water-immiscible, moderately high-boiling solvent.

5. A Q-fluorenyl beta-dia1kylaminoalkanoate, which has the formula wherein Alk is a lower alkylene radical and R and R are lower alkyl radicals.

6. A 9-fluorenyl beta-di(lower alkyl) aminopropionate.

'l. Q-fluorenyl beta-diethylaminopropionate.

8. The process of producing a 9-fiuorenyl betadialkylaminopropionate which comprises esterifying beta-chloropropionic acid with Q-fiuorenol with the simultaneous removal of water by continuous distillation with a water-immiscible, moderately high-boiling solvent, reacting the chloro-ester thus formed with a dialkylamine, and recovering the 9-fiuorenyl beta-dialkylaminopropionate.

9. A basic ester, which has the formula wherein R and R are lower allcgl radicals which may be joined together to form saturated N- heteromonocs'clic radicals haeing 5-6 ring atoms. Allc is a lower allcglene radical and CHAz is a member of the group consisting of beneohydrgl and 9-fluorenyl.

10. An ester of a beta-diallcglaminoalkanoate, which has the formula wherein X is a member of the group consisting of beneohgdrgl and Q-fluorenyl radicals, Allc is a lower allcylene radical and R and R are lower alkyl radicals.

11. A beneohgdryz beta-diallcglaminoallcanoatc. which has the formula wherein Allc is a lower alkylene radical and R and R are lower allcgl radicals.

12. The process of producing an ester of a lower tertiary-aliphatic-aminoallcanoic acid which comprises esterifying a lower haloallcanoic acid with a member of the group consisting of benzohydrol and .Q-fluorenol and reacting the ester thus formed with a secondary aliphatic amine.

13. The process of preparing a basic ester, which has the formula wherein R and R are lower alkyl radicals which may befoined together to form saturated N -heteromonocyclic radicals having 5-6 ring atoms, Alla is a lower allcylene radical and CHAz is a member of the group consisting of beneohydryl and Q-flurorengl, which comprises treating a compound having the formula halogenAllc-COOCHAz with a secondary amine having the formula RRNH, where Allc, CHAz, R and R have the meanings designated hereinabove.

14. The process of preparing a basic ester, which has the formula wherein Allc is a lower allcylene radical and R and R are lower alkyl radicals, which comprises treating a compound having the formula (CsH 5) zCH-O-C'O-Allc-hulogen with a secondary amine having the formula RRNH, where Allc, R and R have the meanings designated hereinabooe.

JOHN W. CUSIC.

RICHARD A. ROBINSON.

REFERENCES CITED The following references are of record in the file of this patent or the original patent:

Fries et a1., Ber. Deut. Chem, vol. 54, page 717 (1921) Righetti, Bull. Societe Chimique de France, vol. 5, Series 5, pages 14664468 (1938).

Petrenko-Kritschenko et al., Zietschrift fur Phys. Chemie, vol. 115, page 298. 

